Combination Therapies for Melanoma

Abstract

Combination Therapy for Melanoma. Disclosed herein is the use of an ATR inhibitor in combination with an immune checkpoint inhibitor to treat melanoma in patients who have previously undergone immunotherapy.

Description

[Technical field]

[0001] The present disclosure relates to a combination of an ATR inhibitor, such as 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (AZD6738, selarasertib, compound (I) below or a pharma- ceutically acceptable salt thereof), and an immune checkpoint inhibitor, such as durvalumab, for use in the treatment of melanoma, administered to a patient who has previously undergone immunotherapy. The present disclosure also relates to a method of treating melanoma involving administration of an ATR inhibitor in combination with an immune checkpoint inhibitor to a patient who has previously undergone immunotherapy, and to the use of an ATR inhibitor in combination with an immune checkpoint inhibitor for the manufacture of a medicament for treating melanoma in a patient who has previously undergone immunotherapy. [ka] [Background technology]

[0002] ATR is a serine / threonine protein kinase and a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family. During normal DNA replication, ATR is recruited at stalled replication forks that may extend into double-stranded breaks if left unrepaired. ATR is also recruited to single-stranded DNA coated with replication protein A (RPA) and then damages the single-stranded DNA or resects the double-stranded break. Recruitment and activation of ATR results in cell cycle arrest in S phase, while DNA is repaired and stalled replication forks disassemble or undergo nuclear fragmentation and programmed cell death (apoptosis).

[0003] As a result, ATR inhibitors are expected to inhibit proliferation in tumor cells that depend on ATR for DNA repair, such as ATM-deficient tumors. In addition to their activity in such monotherapy, ATR inhibitors are also predicted to enhance the activity of cytotoxic DNA damaging agents and radiation therapy (by inhibiting ATR-dependent DNA repair processes) when used in combination.

[0004] Exemplary ATR inhibitors include AZD6738, a potent inhibitor of ATR with good selectivity over other PIKK family members, first disclosed in US Pat. No. 5,399,633. This compound is being developed as an oral antitumor agent in patients with diseases that depend on ATR function for DNA repair, such as tumors deficient in ATM, a serine / threonine-specific protein kinase. AZD6738 is being studied in clinical trials against various forms of cancer.

[0005] Melanoma develops from pigment-producing cells known as melanocytes in the skin and is the most dangerous form of skin cancer. In 2015, 3.1 million people had active melanoma, resulting in 59,800 deaths (Non-Patent Document 1), while the American Cancer Society estimates that in 2020, approximately 100,000 new cases will be diagnosed locally, with approximately 7,000 deaths.

[0006] The current standard of care for melanoma is based on first-line immunotherapy with immune checkpoint inhibitors, such as nivolumab or pembrolizumab. Patients with actionable mutations, such as BRAF mutations, can receive targeted agents. Patients can receive several different lines of immunotherapy, but if this therapy is no longer effective, treatment can continue with standard chemotherapy, such as doublet carboplatin and paclitaxel or single-agent paclitaxel. However, responses to chemotherapy are often poor, with approximately 20% responding to doublet chemotherapy and only approximately 5% responding to taxanes. Therefore, there is an urgent need for further approaches that can be used to treat resistant melanoma cancers that can no longer be addressed by immunotherapy.

[0007] Surprisingly and unexpectedly, analysis of phase II clinical trial data has revealed that ATR inhibitors such as AZD6738 in combination with immune checkpoint inhibitors such as durvalumab are effective in melanoma patients who have been previously treated with immunotherapy, and a high proportion of such individuals respond to subsequent ATR inhibition and immunotherapy. In particular, this combination leads to improved progression-free survival, overall survival, and duration of response. Responses were observed across all melanoma subtypes included, including acral and mucosal melanomas, which are known to be difficult to treat. Furthermore, this combination was found to be effective in patients with primary resistance (and secondary resistance), which is usually difficult to treat. Thus, melanoma patients who have received immunotherapy have been identified as a target population for treatment combining an ATR inhibitor such as AZD6738 with an immune checkpoint inhibitor such as the PD-L1 inhibitor durvalumab.

[0008] Without wishing to be bound by theory, it is believed that ATR inhibitors reset the immune profile of melanoma, thereby sensitizing it to further treatment with immunotherapy. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2011 / 154737 Brochure [Non-patent literature]

[0010] [Non-Patent Document 1] Vos et al.,Lancet 388,1545-1602 Summary of the Invention [Problem to be solved by the invention]

[0011] It is an object herein to provide a combination of an ATR inhibitor, such as AZD6738, with an immune checkpoint inhibitor, such as durvalumab, for the treatment of melanoma in patients who have received prior immunotherapy. [Means for solving the problem]

[0012] In one aspect herein, there is provided a combination comprising an ATR inhibitor and an immune checkpoint inhibitor for use in treating melanoma in a patient who has previously received immunotherapy.

[0013] In a further aspect herein, there is provided a method of treating melanoma in a human or animal patient in need of such treatment who has previously undergone immunotherapy, comprising administering to said patient an effective amount of an ATR inhibitor in combination with an effective amount of an immune checkpoint inhibitor.

[0014] In a further aspect herein there is provided the use of an ATR inhibitor in combination with an immune checkpoint inhibitor in the manufacture of a medicament for treating melanoma, wherein the patient has previously undergone immunotherapy.

[0015] In a further aspect herein, there is provided a combination therapy for use in the treatment of melanoma comprising administering to a human or animal patient undergoing immunotherapy and in need of such therapeutic treatment an effective amount of an ATR inhibitor, optionally with a pharma- ceutically acceptable diluent or carrier, in combination with an effective amount of an immune checkpoint inhibitor, optionally with a pharma- ceutically acceptable diluent or carrier.

[0016] In a further aspect herein, there is provided a kit comprising a pharmaceutical composition comprising an ATR inhibitor and at least one pharma- ceutically acceptable excipient, a pharmaceutical composition comprising an immune checkpoint inhibitor, and instructions for use of the pharmaceutical composition in the treatment of melanoma, wherein the pharmaceutical composition is administered to a patient who has previously undergone immunotherapy. [Brief description of the drawings]

[0017] [Figure 1] 1 is a bar graph showing melanoma patients responding to treatment with a combination of AZD6738 and durvalumab. [Diagram 2] FIG. 1 is a swimmer plot showing the duration of treatment with AZD6738 and durvalumab for melanoma patients along with the patient's response. The "x" on the bar corresponds to the date of first response and the duration of response is calculated from the x. Patient P30 had progressive disease (PD) and no bar is shown as this patient progressed after day 10 and therefore the start and last days of treatment were the same. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The invention detailed herein should not be construed as limited to any of the embodiments or examples listed, as other embodiments will be readily apparent to those of ordinary skill in the art.

[0019] "A" or "an" means "at least one." In any embodiment where "a" or "an" is used to refer to a given element, "a" or "an" can mean one. In any embodiment where "a" or "an" is used to refer to a given element, "a" or "an" can mean one, two, three, four, five, six, seven, eight, nine, or ten.

[0020] When an embodiment includes "a" or "an" element X, a subsequent reference to "the" element X does not mean that there is only one of that element. Rather, the interpretation of "a" or "an" above continues to apply such that "the" also means "at least one." In other words, an embodiment that includes "an element X that is" should be interpreted as "at least one element X that is."

[0021] "Comprising" means that a given material or element may contain other materials or elements. In any embodiment where "comprising" is mentioned, the given material or element may form at least 10% w / w, at least 20% w / w, at least 30% w / w, or at least 40% w / w of the material or element (or combination of materials or elements). In any embodiment where "comprising" is mentioned, "comprising" can also mean "consisting of" (or "consisting of") or "consisting essentially of" (or "consisting essentially of") the given material or element.

[0022] "Consisting of" or "consisting of" means that a given material or element is formed entirely of the material or element (or combination of materials or elements). In any embodiment where "consisting of" or "consisting of" is mentioned, the given material or element may be formed of 100% w / w of the material or element.

[0023] "Consisting essentially of" or "consisting essentially of" means that a given material or element is made up almost entirely of that material or element (or combination of materials or elements). In any embodiment where "consisting essentially of" or "consisting essentially of" is referenced, the given material or element may be formed of at least 50% w / w, at least 60% w / w, at least 70% w / w, at least 80% w / w, at least 90% w / w, at least 95% w / w, or at least 99% w / w of the material or element.

[0024] In any embodiment where "is" or "may be" is used to define a material or element, "is" or "may be" can mean that the material or element "consists of" or "consists essentially of" the material or element.

[0025] When reference is made to "in some embodiments..." in which a particular element may be present, the element may be present in preferred embodiments in the same section or textual region of this specification as well as in preferred embodiments anywhere in this specification.

[0026] When a feature is "selected from" a particular list, the feature may be selected from the list consisting of the specified alternatives (i.e., the list of those alternatives and no other alternatives).

[0027] The claims are embodiments.

[0028] therapeutic use In one embodiment there is provided a combination of an ATR inhibitor and an immune checkpoint inhibitor for use in the treatment of melanoma, the combination being administered to a patient who has previously undergone immunotherapy.

[0029] In one embodiment, there is provided a method of treating melanoma in a human or animal patient in need of such treatment, comprising administering to the patient who has previously undergone immunotherapy an effective amount of an ATR inhibitor in combination with an effective amount of an immune checkpoint inhibitor.

[0030] In one embodiment, there is provided the use of an ATR inhibitor in combination with an immune checkpoint inhibitor in the manufacture of a medicament for treating melanoma, wherein the medicament is administered to a patient who has previously undergone immunotherapy.

[0031] It will be understood that when the term "combination" is used it refers to simultaneous, separate or sequential administration.

[0032] In some embodiments, the combination may be administered simultaneously, separately and / or sequentially.

[0033] In some embodiments, the combination may be administered simultaneously.

[0034] In some embodiments, the combination may be administered separately.

[0035] In some embodiments, the combination may be administered sequentially.

[0036] When the administration of the combination is sequential or separate, the beneficial effect of the combination should not be compromised by delaying the administration of the second component.

[0037] In one embodiment, the ATR inhibitor may be administered prior to the immune checkpoint inhibitor, for example, the ATR inhibitor may be administered 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 24 hours, or 48 hours prior to the immune checkpoint inhibitor.

[0038] In one embodiment, the ATR inhibitor may be administered after the immune checkpoint inhibitor, for example, the ATR inhibitor may be administered 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 24 hours, or 48 hours after the immune checkpoint inhibitor.

[0039] immunotherapy When a patient is "previously immunotherapeutic," it includes patients who have been successfully or unsuccessfully treated with immunotherapy, such that the patient's cancer responded or did not respond to the treatment, respectively. Patients who have been previously immunotherapeutic may have discontinued previous treatment due to ineffective treatment when the immunotherapy did not or no longer successfully addressed the cancer growth or the health impact of the disease. If such treatment was ineffective, the cancer can be described as resistant to immunotherapy. Primary resistance occurs when some inherent feature of the cancer prevents the immunotherapy from working, while acquired resistance, also known as secondary resistance, occurs when the cancer becomes resistant during immunotherapy treatment. Some patients may receive immunotherapy as an adjuvant therapy. Patients who relapse during adjuvant immunotherapy may also be considered to have primary resistance to immunotherapy.

[0040] In some embodiments, the patient's cancer may be resistant to immunotherapy. In some embodiments, the patient's cancer may be resistant to immunotherapy with a PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor. In some embodiments, the patient's cancer may be resistant to immunotherapy with a PD-1 inhibitor. In some embodiments, the patient's cancer may be resistant to immunotherapy with a PD-L1 inhibitor. In some embodiments, the patient's cancer may be resistant to immunotherapy with a CTLA-4 inhibitor.

[0041] In some embodiments, the patient has primary resistance to immunotherapy. In some embodiments, the patient has primary resistance to immunotherapy with a PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor. In some embodiments, the patient has primary resistance to immunotherapy with a PD-1 inhibitor. In some embodiments, the patient has primary resistance to immunotherapy with a PD-L1 inhibitor. In some embodiments, the patient has primary resistance to immunotherapy with a CTLA-4 inhibitor. In one embodiment, primary resistance is defined according to the recommendations of the American Society for Immunotherapy of Cancer (SITC) as having >6 weeks of immunotherapy exposure and a best response of progressive disease or stable disease for less than 6 months before progression.

[0042] In some embodiments, the patient has acquired (or secondary) resistance to immunotherapy. In some embodiments, the patient has acquired resistance to immunotherapy with a PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor. In some embodiments, the patient has acquired resistance to immunotherapy with a PD-1 inhibitor. In some embodiments, the patient has acquired resistance to immunotherapy with a PD-L1 inhibitor. In some embodiments, the patient has acquired resistance to immunotherapy with a CTLA-4 inhibitor. In one embodiment, acquired resistance is defined according to SITC recommendations as having >6 weeks of exposure to immunotherapy and a best response of complete response, partial response, or stable disease for >6 months before progression.

[0043] "Immunotherapy" refers to the use of a patient's own immune system to treat disease, such as cancer. Immunotherapy includes stimulating the natural defenses of a patient's immune system so that it becomes better at finding and attacking harmful species in the body (e.g., cancer cells), as well as administering drugs that act like immune system components to restore or improve the immune system's ability to defend the body (e.g., to find and attack cancer cells).

[0044] In some embodiments, the patient has received at least one form of immunotherapy for a minimum of 6 weeks prior to treatment with the combinations described herein. In some embodiments, the immunotherapy may include immune checkpoint inhibitors, chimeric antigen receptor T cell therapy, cytokine therapy, immunomodulatory drug therapy, cancer vaccine therapy, monoclonal antibody therapy, and / or oncolytic virus therapy.

[0045] "Checkpoint inhibitors" include any substance that blocks immune checkpoints: key regulators of the immune system that, when stimulated, can dampen the immune response to immune stimuli. Some cancers are able to defend themselves against attack by stimulating immune checkpoint targets, so checkpoint therapies are used that can block inhibitory checkpoints and restore immune system function.

[0046] Exemplary checkpoint inhibitors include PD-1 inhibitors (e.g., pembrolizumab [Keytruda®], nivolumab [Opdivo®], cemiplimab [Libtayo®], spartalizumab [PDR001], camrelizumab [SHR1210], sintilimab [IBI308], tislelizumab [BGB-A317], toripalimab [JS 001], AMP-224 or AMP-514), PD-L1 inhibitors (e.g., atezolizumab [Tecentriq®], avelumab [Bavencio®], durvalumab [MEDI4736, Imfinzi®], KN035, CK-301, AUNP12, CA-170 or BMS-986189) and CTLA-4 inhibitors (e.g., ipilimumab [Yervoy®] or tremelimumab).

[0047] In some embodiments, immunotherapy may include treatment with an immune checkpoint inhibitor.

[0048] In some embodiments, immunotherapy may include treatment with an immune checkpoint inhibitor selected from a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor.

[0049] In some embodiments, immunotherapy may include treatment with an immune checkpoint inhibitor that is a PD-1 inhibitor.

[0050] In some embodiments, immunotherapy may include treatment with an immune checkpoint inhibitor that is a PD-L1 inhibitor.

[0051] In some embodiments, immunotherapy may include treatment with an immune checkpoint inhibitor that is a CTLA-4 inhibitor.

[0052] In some embodiments, immunotherapy may include treatment with an immune checkpoint inhibitor selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab.

[0053] In some embodiments, immunotherapy may include treatment with an immune checkpoint inhibitor selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab, and ipilimumab.

[0054] In some embodiments, immunotherapy may include treatment with an immune checkpoint inhibitor selected from pembrolizumab and nivolumab.

[0055] In some embodiments, the immunotherapy may include chimeric antigen receptor T cell therapy.

[0056] Chimeric antigen receptor (CAR) T-cell therapy involves taking some T cells from a patient's blood, mixing them with a special virus that teaches the T cells how to attack tumor cells, and then giving the cells back to the patient so they can find, attack, and kill the cancer.

[0057] In some embodiments, immunotherapy may include treatment with cytokines.

[0058] "Cytokines" are small proteins that transmit messages between cells and stimulate immune cells to attack cancer.

[0059] In some embodiments, immunotherapy may include treatment with an immunomodulatory agent.

[0060] "Immunomodulatory agents" are drugs that generally boost parts of the immune system to treat certain types of cancer.

[0061] In some embodiments, immunotherapy may include treatment with a cancer vaccine.

[0062] A "cancer vaccine" is a substance put into the body to mount an immune response against cancer. Cancer vaccines can be used preventatively, or to boost the body's immune response, allowing for more effective treatment.

[0063] In some embodiments, immunotherapy may include treatment with monoclonal antibodies.

[0064] A "monoclonal antibody (mAb or MoAb)" is an artificial version of an immune system protein. Monoclonal antibodies can be designed to attack very specific parts of cancer cells.

[0065] In some embodiments, immunotherapy may include treatment with an oncolytic virus.

[0066] "Oncolytic virus" therapy uses viruses that have been modified in the laboratory to infect and kill specific tumor cells.

[0067] In some embodiments, immunotherapy may include treatment with one immunotherapeutic agent.

[0068] In some embodiments, immunotherapy may include treatment with two or more immunotherapeutic agents, for example, a PD-L1 antibody or a PD-1 antibody in combination with a CTLA-4 antibody, such as nivolumab in combination with ipilimumab.

[0069] ATR inhibitors An "ATR inhibitor" is any compound that attenuates the activity of the ATR enzyme in vitro or in vivo. ATR inhibitors can be selective or non-selective and can be small molecules or biomolecules.

[0070] Exemplary ATR inhibitors include AZD6738, M6620 (berzosertib), BAY-1895344, EPT-46464, VE-821, and VX-970.

[0071] In some embodiments, the ATR inhibitor may be selected from the group consisting of AZD6738, M6620, BAY-1895344, EPT-46464, VE-821, and VX-970.

[0072] In some embodiments, the ATR inhibitor can be AZD6738.

[0073] In some embodiments, AZD6738 can be compound (I) or a pharma- ceutically acceptable salt thereof.

[0074] The term "pharmaceutical acceptable" is used to specify that the subject (e.g., salt, dosage form, or excipient) is suitable for use in patients and / or has clinical or commercial priority. Exemplary lists of pharmaceutical acceptable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use", P.H. Stahl and C.G. Wermuth, editors, Weinheim / Zurich: Wiley-VCH / VFiCA, 2002 or subsequent editions.

[0075] In some embodiments, AZD6738 can be Compound (I) in a salt free form (eg, a neutral or zwitterionic form or, for example, a free base or free acid form).

[0076] In some embodiments, AZD6738 can be a pharma- ceutically acceptable salt of Compound (I).

[0077] Suitable pharma- ceutically acceptable salts of compound (I) are, for example, acid addition salts. Acid addition salts of compound (I) can be formed by contacting the compound with a suitable inorganic or organic acid under conditions known to those skilled in the art.

[0078] Acid addition salts may be formed with inorganic acids selected from, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and also with organic acids selected from, for example, citric acid, fumaric acid, maleic acid, and methanesulfonic acid.

[0079] Further suitable pharma- ceutically acceptable salts of compound (I) are, for example, salts which are formed in the human or animal body after administration of compound (I) to said body.

[0080] In some embodiments, the ATR inhibitor can be AZD6738 and is administered according to a 2 weeks on / 2 weeks off (14 days on / 14 days off) schedule within a 28 day cycle.

[0081] In some embodiments, the ATR inhibitor may be AZD6738 and is administered for 14 consecutive days within a 28 day cycle.

[0082] In some embodiments, the ATR inhibitor can be AZD6738 and is administered on days 1-14 of a 28 day cycle.

[0083] In some embodiments, the ATR inhibitor can be AZD6738 and is administered on days 15 to 28 of a 28 day cycle.

[0084] In some embodiments, the ATR inhibitor can be AZD6738 and is administered according to a 1 week on / 3 weeks off schedule (7 days on / 21 days off) within a 28 day cycle.

[0085] In some embodiments, the ATR inhibitor can be AZD6738, administered for 7 consecutive days within a 28 day cycle.

[0086] In some embodiments, the ATR inhibitor can be AZD6738 and is administered on days 1-7 of a 28 day cycle.

[0087] A "28-day cycle" is a single treatment period that may be repeated continuously for a given patient or with treatment intervals (e.g., of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 30, or 60 days) between individual cycles.

[0088] In some embodiments, the ATR inhibitor can be AZD6738, administered in a total daily dose of 30 mg to 500 mg.

[0089] In some embodiments, the ATR inhibitor can be AZD6738 and is administered at a total daily dose of 40 mg, 60 mg, 80 mg, 160 mg, 240 mg, 320 mg or 480 mg.

[0090] In some embodiments, the ATR inhibitor can be AZD6738, administered at a total daily dose of 480 mg.

[0091] In some embodiments, the ATR inhibitor can be AZD6738, administered at a dose of 240 mg twice daily (i.e., a total daily dose of 480 mg administered in two divided portions, each of 50% of the total daily dose, also referred to as 240 mg BID).

[0092] In some embodiments, the ATR inhibitor can be AZD6738, administered at a total daily dose of 320 mg.

[0093] In some embodiments, the ATR inhibitor can be AZD6738, administered at a dose of 160 mg twice daily (i.e., a total daily dose of 160 mg administered in two divided portions, each of 50% of the total daily dose, also referred to as 160 mg BID).

[0094] In some embodiments, the ATR inhibitor can be AZD6738, administered twice daily on a 2 weeks on / 2 weeks off schedule within a 28 day cycle.

[0095] In some embodiments, the ATR inhibitor can be AZD6738, administered twice daily at a dose of 240 mg on a 2 week on / 2 week off schedule within a 28 day cycle.

[0096] In some embodiments, the ATR inhibitor can be AZD6738, administered twice daily at a dose of 240 mg for 14 consecutive days within a 28 day cycle.

[0097] In some embodiments, the ATR inhibitor can be AZD6738 administered at a dose of 240 mg twice daily on days 1-14 of a 28 day cycle.

[0098] In some embodiments, the ATR inhibitor can be AZD6738 administered at a dose of 240 mg twice daily on days 15-28 of a 28 day cycle.

[0099] In some embodiments, the ATR inhibitor can be AZD6738 administered twice daily at a dose of 160 mg on a 2 week on / 2 week off schedule within a 28 day cycle.

[0100] In some embodiments, the ATR inhibitor can be AZD6738, administered twice daily at a dose of 160 mg for 14 consecutive days within a 28 day cycle.

[0101] In some embodiments, the ATR inhibitor can be AZD6738 administered twice daily at a dose of 160 mg on days 1-14 of a 28 day cycle.

[0102] In some embodiments, the ATR inhibitor can be AZD6738 administered twice daily at a dose of 160 mg on days 15-28 of a 28 day cycle.

[0103] In some embodiments, the ATR inhibitor can be AZD6738, administered twice daily on a 1 week on / 3 weeks off (7 days on / 21 days off) schedule within a 28 day cycle.

[0104] In some embodiments, the ATR inhibitor can be AZD6738, administered twice daily at a dose of 240 mg on a 1 week on / 3 weeks off schedule within a 28 day cycle.

[0105] In some embodiments, the ATR inhibitor can be AZD6738, administered twice daily at a dose of 240 mg for 7 consecutive days within a 28 day cycle.

[0106] In some embodiments, the ATR inhibitor can be AZD6738 administered twice daily at a dose of 240 mg on days 1-7 of a 28 day cycle.

[0107] In some embodiments, the ATR inhibitor can be AZD6738 administered twice daily at a dose of 160 mg on a 1 week on / 3 weeks off schedule within a 28 day cycle.

[0108] In some embodiments, the ATR inhibitor can be AZD6738, administered twice daily at a dose of 160 mg for 7 consecutive days within a 28 day cycle.

[0109] In some embodiments, the ATR inhibitor can be AZD6738 administered twice daily at a dose of 160 mg on days 1-7 of a 28 day cycle.

[0110] Immune checkpoint inhibitors "Checkpoint inhibitor" is defined in paragraphs

[0044] and

[0045] .

[0111] In some embodiments, the immune checkpoint inhibitor is administered in combination with an ATR inhibitor selected from a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor.

[0112] In some embodiments, the immune checkpoint inhibitor can be a PD-1 inhibitor.

[0113] In some embodiments, the immune checkpoint inhibitor may be a PD-L1 inhibitor.

[0114] In some embodiments, the immune checkpoint inhibitor can be a CTLA-4 inhibitor.

[0115] In some embodiments, the immune checkpoint inhibitor may be selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab.

[0116] In some embodiments, the immune checkpoint inhibitor can be the PD-L1 inhibitor durvalumab or an antigen-binding fragment thereof. In some embodiments, the immune checkpoint inhibitor can be durvalumab.

[0117] Durvalumab is a human monoclonal antibody against human PD-L1 that can inhibit PD-L1 binding to both PD1 and CD80 receptors. Disclosures related to durvalumab can be found in U.S. Patent Nos. 8,779,108 and 9,493,565, which are incorporated herein by reference.

[0118] Durvalumab and antigen-binding fragments thereof for use in therapy provided herein comprise a heavy chain and a light chain or a heavy chain variable region and a light chain variable region. In some embodiments, durvalumab or antigen-binding fragments thereof for use in therapy provided herein comprise a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, durvalumab or antigen-binding fragments thereof for use in therapy provided herein comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the CDR1, CDR2 and CDR3 sequences defined by Kabat in SEQ ID NOs: 3-5, and the light chain variable region comprises the CDR1, CDR2 and CDR3 sequences defined by Kabat in SEQ ID NOs: 6-8. A person skilled in the art can readily identify the Chothia definition, the Abm definition, or other CDR definitions known to those of skill in the art. In some embodiments, durvalumab or an antigen-binding fragment thereof for use in the treatments provided herein comprises the variable heavy and variable light chain CDR sequences of the 2.14H9OPT antibody disclosed in U.S. Pat. Nos. 8,779,108 and 9,493,565, which are incorporated by reference in their entireties.

[0119] In some embodiments, the immune checkpoint inhibitor can be durvalumab and is administered every 4 weeks starting on day 1 of cycle 1.

[0120] In some embodiments, the immune checkpoint inhibitor may be durvalumab and is administered in an amount of 1500 mg.

[0121] In some embodiments, the immune checkpoint inhibitor can be durvalumab, administered once every 4 weeks (28 days) starting on day 1 of cycle 1 in an amount of 1500 mg (Q28D).

[0122] In some embodiments, the CTLA-4 inhibitor is tremelimumab or an antigen-binding fragment thereof. Tremelimumab or an antigen-binding fragment thereof for use in a treatment provided herein comprises a heavy chain and a light chain or a heavy chain variable region and a light chain variable region. In some embodiments, tremelimumab or an antigen-binding fragment thereof for use in a treatment provided herein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, tremelimumab or an antigen-binding fragment thereof for use in a treatment provided herein comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the CDR1, CDR2 and CDR3 sequences defined by Kabat in SEQ ID NOs: 11-13, and the light chain variable region comprising the CDR1, CDR2 and CDR3 sequences defined by Kabat in SEQ ID NOs: 14-16. A person skilled in the art can readily identify the Chothia definition, the Abm definition, or other CDR definitions known to those skilled in the art. In some embodiments, tremelimumab or an antigen-binding fragment thereof for use in the treatments provided herein comprises the variable heavy and variable light chain CDR sequences of the 11.2.1 antibody disclosed in U.S. Pat. No. 6,682,736, the entire contents of which are incorporated herein by reference.

[0123] The term "antibody", as used herein, refers to a protein capable of recognizing and specifically binding to an antigen. A normal or conventional mammalian antibody is a tetramer, typically composed of two identical pairs of polypeptide chains, each pair consisting of one "light" chain (typically having a molecular weight of about 25 kDa) and one "heavy" chain (typically having a molecular weight of about 50-70 kDa). The terms "heavy chain" and "light chain", as used herein, refer to any immunoglobulin polypeptide having sufficient variable domain sequence to confer specificity for a target antigen. The amino-terminal portion of each light chain and each heavy chain typically contains a variable domain of about 100-110 or more amino acids that is typically involved in antigen recognition. The carboxyl-terminal portion of each chain typically defines a constant domain that is involved in effector function. Thus, in naturally occurring antibodies, the full-length heavy chain immunoglobulin polypeptide contains a variable domain (V H ) and three constant domains (C H1 , C H2 and C H3 ) and C H1 and C H2 and a hinge region between the V H The domain is located at the amino terminus of the polypeptide and is H3 The domains are located at the carboxyl terminus, and full-length light chain immunoglobulin polypeptides contain a variable domain (V L ) and the constant domain (C L ), including V L The domain is located at the amino terminus of the polypeptide and is L The domain is present at the carboxyl terminus.

[0124] Within full-length light and heavy chains, the variable and constant domains are typically joined by a "J" region of about 12 or more amino acids, and in the heavy chain also includes a "D" region of about 10 or more amino acids. The variable regions of each light / heavy chain pair typically form the antigen-binding site. The variable domains of naturally occurring antibodies typically exhibit relatively conserved framework regions (FR) of identical overall structure linked by three hypervariable regions, also called complementarity determining regions or CDRs. The CDRs from the two chains of each pair are typically aligned by the framework regions, which may enable binding to a specific epitope. From the amino terminus to the carboxyl terminus, the variable domains of both light and heavy chains typically include the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.

[0125] The term "antigen-binding fragment" refers to a portion of an intact antibody and / or to the antigen-determining variable domain of the intact antibody. It is known that the antigen-binding function of an antibody can be performed by a fragment of a full-length antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2 and Fv fragments, linear antibodies, single-chain antibodies, diabodies and multispecific antibodies (formed from antibody fragments).

[0126] melanoma "Cancer" is used herein synonymously with tumors and lesions. Cancer can include primary cancers as well as secondary cancers and metastases. Tumors can be detectable or undetectable, e.g., micrometastases.

[0127] "Treatment of melanoma," "treating melanoma," and similar terms encompass treating existing melanoma cancer and / or preventing melanoma cancer. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment of a susceptible individual may begin before symptoms develop (e.g., due to medical history and / or taking into account genetic or other susceptibility factors). Treatment may be continued after symptoms have resolved, e.g., to present or delay the recurrence of symptoms.

[0128] In some embodiments, treating melanoma or treating melanoma can refer to treating and preventing melanoma.

[0129] In some embodiments, treating melanoma or treating melanoma can mean curing melanoma.

[0130] In some embodiments, treating melanoma or treating melanoma can mean preventing melanoma.

[0131] Mucosal and acral melanoma are known to be particularly difficult histologic subtypes of melanoma to treat, however responses in these subtypes have been observed in patients treated with the therapies described herein.

[0132] In some embodiments, the melanoma can be cutaneous melanoma.

[0133] In some embodiments, the melanoma can be cutaneous anal melanoma.

[0134] In some embodiments, the melanoma can be an acral melanoma.

[0135] In some embodiments, the melanoma can be a mucosal melanoma.

[0136] In some embodiments, the melanoma can be early stage melanoma, actively progressing melanoma, progressive (eg, locally advanced) melanoma, invasive melanoma, metastatic melanoma, and / or drug resistant melanoma.

[0137] In some embodiments, the melanoma can be locally advanced melanoma.

[0138] In some embodiments, the melanoma can be advanced and / or metastatic melanoma.

[0139] In some embodiments, the melanoma can be an aggressive melanoma.

[0140] In some embodiments, the melanoma can be locally advanced melanoma and / or metastatic melanoma.

[0141] In some embodiments, the melanoma can be metastatic melanoma.

[0142] In some embodiments, the melanoma can be an invasive melanoma.

[0143] In some embodiments, the melanoma can be stage IV melanoma.

[0144] In some embodiments, the melanoma can be unresectable melanoma. In some embodiments, the melanoma can be stage III unresectable melanoma.

[0145] Patient Selection In some embodiments, the melanoma cancer may be deficient in ATM.

[0146] When a melanoma cancer is "ATM deficient," the cancer cells express less ATM protein than normal non-cancerous cells of the same type. For example, when analyzed by IHC protein staining, the cancer cells may express <5%, <10%, <20%, <30%, <40%, <50%, <60%, <70%, <80%, <90%, or <100% of the total ATM protein typically expressed by normal cells of the same type. ATM deficient melanoma cancer cells may also contain deleterious mutations in both alleles of the ATM gene.

[0147] In some embodiments, the melanoma cancer may be defective in ARID1A.

[0148] When a melanoma cancer is "ARID1A deficient," the cancer cells express less ARID1A protein than normal non-cancerous cells of the same type. For example, when analyzed by IHC protein staining, the cancer cells may express ≦5%, ≦10%, ≦20%, ≦30%, ≦40%, ≦50%, ≦60%, ≦70%, ≦80%, ≦90%, or ≦100% of the total ARID1A protein typically expressed by normal cells of the same type. ARID1A deficient melanoma cancer cells may also contain a mutation (e.g., a loss-of-function mutation, such as a nonsense mutation) in the ARID1A gene.

[0149] In some embodiments, the melanoma can be an ATM-deficient melanoma.

[0150] In some embodiments, the melanoma can be an ARID1A-deficient melanoma.

[0151] The current standard of care for melanoma is first line immunotherapy, therefore the combinations described herein may be administered to patients as second or third line therapy.

[0152] In some embodiments, the combination is administered to a patient as a second line therapy, ie, after the patient has failed a prior immunotherapy.

[0153] In some embodiments, the combination is administered to a patient as a third line therapy. Patients receiving the combination as a third line therapy may be treated with BRAF and MEK inhibitors, such as dabrafenib and trametinib, prior to treatment with the immunotherapy.

[0154] Clinical characteristics In one embodiment there is provided an ATR inhibitor such as AZD6738 in combination with an immune checkpoint inhibitor such as durvalumab for use in the treatment of melanoma, wherein the ATR inhibitor and the immune checkpoint inhibitor are administered to a patient who has previously undergone immunotherapy, and the treatment with the combination achieves a response rate of between 10%-50%, between 10%-40%, between 10%-35%, between 20%-35%, between 25%-40%, between 30%-35%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60% or greater than 70%.

[0155] "Response rate" is the proportion of patients with measurable disease at baseline who achieved at least one response, ie, complete or partial response to treatment by RECIST.

[0156] The "RECIST criteria" (e.g., RECIST 1.1 criteria) are detailed at the following site: https: / / recist.eortc.org / and described in Eur. J. Cancer 2016, 62, Pages 132-137.

[0157] In one embodiment there is provided an ATR inhibitor such as AZD6738 in combination with an immune checkpoint inhibitor such as durvalumab for use in the treatment of melanoma, wherein the ATR inhibitor and the immune checkpoint inhibitor are administered to a patient who has previously undergone immunotherapy, and the combination treatment achieves a clinical benefit rate of between 25% and 100%, between 25% and 90%, between 40% and 80%, or between 50% and 70%.

[0158] "Clinical benefit rate" is the response rate calculated by adding the proportion of patients whose best response was stable disease at first scan, i.e., who had no disease progression at first scan (complete response + partial response + stable disease).

[0159] In one embodiment there is provided an ATR inhibitor such as AZD6738 in combination with an immune checkpoint inhibitor such as durvalumab for use in the treatment of melanoma, wherein the ATR inhibitor and the immune checkpoint inhibitor are administered to a patient who has previously received immunotherapy, and the combination treatment achieves a progression free survival of greater than 3 months, greater than 4 months, greater than 5 months, greater than 6 months, preferably greater than 7 months.

[0160] "Progression-free survival" or "PFS" is the length of time during and after treatment that a patient lives without their disease getting worse. PFS can be measured using the Kaplan-Meier method.

[0161] In one embodiment there is provided an ATR inhibitor such as AZD6738 in combination with an immune checkpoint inhibitor such as durvalumab for use in the treatment of melanoma, wherein the ATR inhibitor and the immune checkpoint inhibitor are administered to a patient who has previously received immunotherapy, and the combination treatment achieves an overall survival of greater than 10 months, greater than 11 months, greater than 12 months, greater than 13 months, preferably greater than 14 months.

[0162] "Overall survival" or "OS" is the length of time from the start of treatment that a patient remains alive.

[0163] In one embodiment there is provided an ATR inhibitor such as AZD6738 in combination with an immune checkpoint inhibitor such as durvalumab for use in the treatment of melanoma, wherein the ATR inhibitor and the immune checkpoint inhibitor are administered to a patient who has previously undergone immunotherapy, and the combination treatment achieves a duration of response of at least 3 months, at least 4 months, at least 5 months, preferably at least 6 months.

[0164] "Duration of response" or "DoR" is the length of time that a tumor continues to respond to treatment without the cancer growing or spreading.

[0165] In one embodiment there is provided a combination of an ATR inhibitor, such as AZD6738, and an immune checkpoint inhibitor, such as durvalumab, for use in the treatment of melanoma, wherein the combination is administered to a patient who has received prior immunotherapy, and wherein treatment with the combination does not cause any serious side effects in the melanoma patient.

[0166] In some embodiments, a serious side effect may be defined as a grade 4 or 5 adverse event.

[0167] "Grade 4 or 5 adverse events" can be classified according to the Common Terminology Criteria for Adverse Events (CTCAE).

[0168] kit In one aspect, a) a first pharmaceutical composition comprising an ATR inhibitor and a pharma- ceutical acceptable excipient; b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and a pharma- ceutically acceptable excipient; and c) instructions for use of the first and second pharmaceutical compositions in the treatment of melanoma in a patient who has previously undergone immunotherapy; and A kit is provided comprising:

[0169] In one embodiment, the ATR inhibitor may be AZD6738.

[0170] In one embodiment, the immune checkpoint inhibitor may be selected from a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor.

[0171] In some embodiments, the immune checkpoint inhibitor may be selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab.

[0172] In some embodiments, the immune checkpoint inhibitor may be durvalumab.

[0173] In one embodiment, the ATR inhibitor is AZD6738 and the immune checkpoint inhibitor is durvalumab.

[0174] Specific embodiments In one embodiment, there is provided an ATR inhibitor for use in the treatment of melanoma, wherein the ATR inhibitor is AZD6738, administered in combination with an immune checkpoint inhibitor to a patient who has previously received therapy with an immune checkpoint inhibitor.

[0175] In one embodiment there is provided an ATR inhibitor for use in the treatment of melanoma, wherein the ATR inhibitor is AZD6738 and is administered in combination with a PD-L1 inhibitor to a patient who has previously received immune checkpoint inhibitor therapy selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab.

[0176] In one embodiment there is provided an ATR inhibitor for use in the treatment of melanoma, wherein the ATR inhibitor is AZD6738 and is administered in combination with durvalumab to a patient who has previously received therapy with an immune checkpoint inhibitor selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab and tremelimumab.

[0177] In one embodiment there is provided an ATR inhibitor for use in the treatment of melanoma, wherein the ATR inhibitor is AZD6738, administered in combination with durvalumab to a patient who has previously received therapy with an immune checkpoint inhibitor selected from pembrolizumab and nivolumab. EXAMPLES

[0178] Abbreviation AE - Adverse Event ATM - ataxia telangiectasia mutated ATR - Ataxia telangiectasia and Rad3 related protein BD - Twice a day CRF - Case Report Form (Electronic / Paper) CTCAE - Common Terminology Criteria for Adverse Events ctDNA - circulating tumor DNA DNA - Deoxyribonucleic Acid ECG - Electrocardiogram MSI - microsatellite unstable tumor MSS - microsatellite stable tumor SAE - Serious Adverse Event

[0179] Clinical Trial Protocol Introduction: This was a multicenter Phase II study of AZD6738 in combination with durvalumab in patients with refractory solid tumors. Tumor types studied were: gastric cancer in second line and beyond (outside the scope of this specification) and metastatic melanoma that progressed after standard treatment. Patients received a combined regimen of AZD6738 plus durvalumab. A total of 60 patients (30 per tumor type) have been fully recruited in this study, but follow-up is ongoing. AZD6738 was administered BD at 240 mg on days 15-28 of a 28-day cycle. Durvalumab was administered at a fixed dose of 1500 mg every 4 weeks starting on day 1 of cycle 1. Tumor assessments using modified RECIST 1.1 were performed at screening (within 28 days prior to first dose) and every 8 weeks from the date of first dose up to week 40, then every 12 weeks (within a time frame of ±7 days from the scheduled date) until objective disease progression. Study treatment was continued until objective disease progression (unless other criteria for treatment discontinuation were met). Patients could continue AZD6738 and durvalumab after progression (by modified RECIST 1.1) at the discretion of the investigator if they were clinically benefiting from treatment and did not meet any other discontinuation criteria. However, continuation of either AZD6738 or durvalumab as monotherapy was not permitted. If patients discontinued study treatment before disease progression, they were required to continue evaluations using modified RECIST 1.1 until disease progression and then follow-up for survival. Survival assessments were performed every 8 weeks after objective disease progression. After treatment discontinuation, details of the initial and subsequent cancer treatments were collected. Imaging modalities used for evaluation of revised RECIST 1.1 were CT or MRI scans of the chest, abdomen, and pelvis. Revised RECIST 1.1 scans were analyzed by the on-site investigator. Patients were also asked to provide tumor samples from primary or metastatic tumors at the time of progression. Donation of samples was not optional, but contingent on specific consent, and will aid in understanding resistance mechanisms. However, the protocol allowed for waiving the repeat biopsy procedure if a biopsy site was not available.

[0180] Primary objectives and evaluation items:

[0181] [Table 1]

[0182] Secondary Objectives and Endpoints:

[0183] [Table 2]

[0184] Third objective and evaluation item:

[0185] [Table 3]

[0186] Target Population: There are two cohorts in this study, with Cohort A being outside the scope of this specification.

[0187] Cohort A: Patients with refractory gastric cancer who had failed treatment with second-line chemotherapy for progressive disease were enrolled. Patients must have had imaging-confirmed progression on prior chemotherapy to treat gastric cancer with at least one measurable lesion according to revised RECIST 1.1. Prior adjuvant / neoadjuvant chemotherapy was permitted if completed ≥6 months prior to starting first-line treatment. No prior exposure to AZD6738 was permitted.

[0188] Cohort B: Patients with metastatic melanoma who had failed prior anti-PD(L)1 therapy were enrolled. Anti-PD(L)1 therapy had to be the most recent regimen prior to study entry.

[0189] Treatment duration: Patients continued to receive study treatment until they demonstrated objective disease progression (as determined by modified RECIST 1.1) or met any other discontinuation criteria. There was no maximum treatment duration for AZD6738 and durvalumab. At the investigator's discretion, patients could continue AZD6738 and durvalumab after objective disease progression (as determined by modified RECIST 1.1) if they were clinically benefiting from treatment and did not meet any other discontinuation criteria. Patients continued to receive treatment with AZD6738 and durvalumab, provided that treatment was tolerable, there was evidence of clinical benefit (as determined by the investigator), and drug supplies were secured. Both durvalumab and AZD6738 were discontinued upon confirmation of objective disease progression or upon meeting of treatment discontinuation criteria. If either durvalumab and / or AZD6738 was deemed to be intolerable (as judged by the investigator) and, as a result, discontinuation of either agent was deemed to be in the patient's best interest despite dose interruptions, dose modifications and initiation of supportive care, both durvalumab and AZD6738 were discontinued and the patient was withdrawn from the study. Patients were not permitted to continue either durvalumab or AZD6738 as monotherapy. There was no maximum treatment duration for AZD6738 and durvalumab.

[0190] Treatment period, investigational drug, dosage and administration method AZD6738 was administered at 240 mg bd on days 15-28 of a 28-day cycle. Durvalumab was administered at 1500 mg every 4 weeks starting on day 1 of cycle 1.

[0191] statistical methods Cohort A (gastric cancer): The primary endpoint of the study was ORR (cohort A and cohort B were analyzed separately). The sample size was calculated using Simon's two-stage minimax design to limit type I error to 5% for the null hypothesis of a true response of 15% or less for an arm, and to have 90% power to detect a true response of 40% or more. Sixteen evaluable patients were to be treated in the first stage. If two or fewer responses were observed in the first stage, the arm was to be discontinued. If at least three responses were observed in the first stage, 11 additional evaluable patients were to be enrolled in the second stage. In the final analysis, the null hypothesis was to be rejected if at least eight of the 27 evaluable patients responded. RRs were reported with exact 95% confidence intervals.

[0192] Cohort B (melanoma): The sample size was calculated using Simon's two-stage minimax design to limit type I error to 5% for the null hypothesis that true responses to an arm were 15% or less, and to have 90% power to detect true responses of 40% or more. Sixteen evaluable patients were to be treated in the first stage. If there were two or fewer responses in the first stage, the arm was to be discontinued. If there were at least three responses in the first stage, 11 additional evaluable patients were to be enrolled in the second stage. In the final analysis, the null hypothesis was to be rejected if at least eight of the 27 evaluable patients responded. RRs were reported with exact 95% confidence intervals.

[0193] Inclusion Criteria: Patients were eligible to be included in the study only if all of the following inclusion criteria and none of the exclusion criteria were met. 1. Full informed consent has been provided prior to any study-specific procedures. 2. Patient's age is ≥ 18 years. 3. ATM-deficient or ATM-nondeficient patients by IHC. ATM expression status was prospectively evaluated. A minimum number of patients from each group (ATM-nondeficient and ATM-deficient) was required for analysis, and this number was ensured by conducting prospective screening at our institution. 4. Weight must be >30kg. 5. Cohort A: Advanced stage, confirmed histological or cytological diagnosis of gastric adenocarcinoma (including GEJ) (confirmed by imaging) that has progressed after failure of second-line chemotherapy. 6. Cohort B: Confirmed melanoma (metastatic) that progressed prior to anti-PD(L)1 therapy (immediately prior to regimen). 7. Presence of measurable disease as defined by Response Evaluation Criteria in Solid Tumors (modified RECIST) version 1.1 amenable to accurate repeated measurements. 8. Tumor specimens (either by resection or biopsy) for ATM IHC and other exploratory biomarkers have been provided. 9. Patient is willing and able to comply with the protocol, including treatment and scheduled visits and examinations, for the duration of the study. 10. ECOG performance status 0-1 with no deterioration between screening and first dose of study treatment. 11. Patients had a life expectancy of ≥ 3 months from the proposed date of first dose. 12. Patients who have had a 3-week washout period for any prior treatment before starting study drug. The following intervals must be observed between the end of prior treatment and the first dose of study drug: ≥4 weeks for radiation therapy (patients undergoing palliative radiation for non-target lesions do not need to have a 4-week washout period and can be enrolled immediately); patients may receive a fixed dose of bisphosphonates or denosumab as long as it was started at least 4 weeks prior to treatment; ≥4 weeks for major surgery; ≥7 days for minor surgical procedures; ≥14 days (or 5 half-lives, whichever is longer) for any investigational drug. 13.Subject has acceptable bone marrow, liver, and renal function measured within 28 days prior to receiving study treatment, as defined below: - Hemoglobin ≥ 9.0 g / dL (no blood transfusions allowed within 14 days of study drug administration) - Absolute neutrophil count (ANC) ≥ 1.5 x 109 / L - Platelet count ≥ 100 × 109 / L (transfusion within 14 days of study drug administration is not permitted) - Total bilirubin ≦1.5 × upper limit of normal (ULN) - AST(SGOT) / ALT(SGPT) should be ≤2.5×institutional upper limit of normal if liver metastases are not present, and ≤5×ULN if present - Serum creatinine ≤ 1.5 x institutional ULN - Glomerular filtration rate < 45 mL / min as assessed by standard procedures at the study site - Hematuria: +++ by microscopy or urine dipstick 14. Female patients of childbearing potential who had a negative pregnancy test (urine or serum), were not breastfeeding, and were using adequate contraception. Female patients were using highly effective contraception from screening until 90 days after the last dose of drug. All methods of contraception (except total abstinence) were used in combination with condom use by the male sexual partner in the event of sexual intercourse. Female patients were not of childbearing potential at screening by meeting one of the following criteria: a. Postmenopausal women, defined as being over 50 years of age and having at least 12 months of amenorrhea after cessation of all exogenous hormone therapy. b. Documented irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy (but not tubal ligation). c. Amenorrhea for 12 months and postmenopausal serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and plasma estradiol concentrations within the facility's range. 15. Sexually active male patients must be willing to use barrier contraception, i.e. condoms, with all sexual partners during the study and 1 week after the last dose of study drug. If a sexual partner was a "female of childbearing potential" who was not using effective contraception, the man must have used condoms (containing spermicide) during the study and for 6 months after the last dose of study drug. 16. Require biopsy during pre-treatment screening window and upon progression (require fresh frozen if clinically feasible).

[0194] Exclusion Criteria: Patients were not included in the study if they met any of the following exclusion criteria: 1. Have been diagnosed with ataxia telangiectasia. 2. Any prior treatment with ATR inhibitors, DNA damage repair inhibitors. 3. Any gastrointestinal symptoms, including but not limited to inability to swallow oral medications, refractory nausea and vomiting, chronic gastrointestinal disease or previous significant bowel resection, ileus, or CTCAE grade 3 or grade 4 upper gastrointestinal bleeding within 4 weeks prior to enrollment that would prevent adequate absorption of AZD6738. 4. Active or previously documented autoimmune or inflammatory disease (including IBD [e.g., Crohn's disease, ulcerative colitis, or diverticulitis] within the past 2 years prior to starting treatment, SLE, sarcoidosis syndrome, tuberculosis, Wegener's syndrome, myasthenia gravis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, primary immunodeficiency or history of human immunodeficiency virus infection, known hepatitis B or C infection, history of organ transplant requiring the use of immunosuppressants, glomerulonephritis, nephritic syndrome, Fanconi syndrome, or renal tubular acidosis. Exceptions to this criterion are as follows: - Subjects with vitiligo or alopecia, hypothyroidism stable with hormone replacement (e.g., Hashimoto's syndrome) or psoriasis not requiring systemic treatment; subjects with celiac disease controlled by diet alone and patients with no active disease in the past 5 years may be enrolled after consultation with the principal investigator. 5. Untreated central nervous system (CNS) metastatic disease, leptomeningeal disease, or spinal cord compression. Note: Any subject with previously treated CNS metastases who was asymptomatic, radiographically and neurologically stable for at least 4 weeks, and did not require corticosteroids (at any dose) for symptomatic management for at least 4 weeks prior to the first dose of treatment was not excluded. 6. Patients with a second primary cancer, excluding: adequately treated non-melanoma skin cancer, curatively treated intraepithelial carcinoma of the cervix, or curatively treated other solid tumor with no evidence of disease for ≤ 3 years. 7. Current or previous use of immunosuppressants within 4 weeks prior to the first dose of durvalumab, except for intranasal, topical, and inhaled corticosteroids; systemic corticosteroids in physiological doses not exceeding >10 mg prednisone or equivalent per day. 8. Patients have received any live attenuated vaccine within 30 days prior to study entry or within 30 days after receiving study treatment. 9. You are receiving or have received (within a 5 half-life withdrawal period) concomitant medications, herbal supplements, and / or foods that significantly modulate P450 3A4 (CYP3A4) or Pgp activity. Note that these include common azole antifungals, macrolide antibiotics, and other drugs. 10. Patients with any of the following cardiac criteria: - Heart rate-corrected mean QT interval (QTc) ≥ 470 ms calculated from three electrograms (ECGs) using the Fridericia correction - Any clinically significant abnormality in rhythm, conduction, or morphology of the resting ECG, e.g., complete left bundle branch block, third degree heart block, second degree heart block - Any factor that increases the risk of QTc prolongation or the risk of arrhythmic events, such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or sudden unexplained death in patients under 40 years of age, or concomitant medications known to prolong the QT interval. - Uncontrolled hypotension: Clinically relevant orthostatic hypotension including systolic BP < 90mmHg and / or diastolic BP 60mmHg or a drop in blood pressure of > 20mmHg - Atrial fibrillation with a heart rate >100 bpm on resting ECG - Symptomatic heart failure (NYHA grade II to IV) - Known impaired LVEF <55% - Previous or current cardiomyopathy - Severe valvular heart disease - Uncontrolled angina (Canadian Cardiovascular Society grade II-IV, regardless of medical therapy) - Stroke or transient ischemic attack in the last 6 months prior to screening - Acute coronary syndrome within 6 months prior to starting treatment. 11. Any of the following ophthalmologic conditions: intraocular pressure >21 mmHg or poorly controlled glaucoma (unrelated to intraocular pressure), current or previous history of central serous retinopathy or retinal vein occlusion 12. Any evidence of severe or poorly controlled systemic disease, including active infection (requiring antibiotics, antifungals or antivirals), diabetes mellitus types I and II, poorly controlled seizures, bleeding diathesis, severe COPD, severe Parkinson's disease 13. Any unresolved toxicity NCI CTCAE grade ≥2 from prior anticancer therapy, excluding alopecia, vitiligo, or major surgical procedures (as defined by the investigator), within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative purposes was permitted. 14.Female patients who are pregnant or lactating from screening through 90 days after the last dose of durvalumab monotherapy, or male or female patients of reproductive potential who are not intending to use effective birth control. 15. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. 16. Restrictions For durvalumab: - Patients must not donate blood while participating in the study or for at least 90 days after their last durvalumab infusion. - Immunosuppressant medications were prohibited, including, but not limited to, systemic corticosteroids at doses greater than 10 mg / day of prednisone or equivalent, methotrexate, azathioprine, and tumor necrosis factor alpha blockers. Use of immunosuppressant medications to manage study drug-related AEs and in patients with contrast allergy was permitted. In addition, use of inhaled and intranasal corticosteroids was permitted. - Live attenuated vaccines within 30 days of durvalumab treatment (i.e., 30 days prior to the first dose, during treatment with durvalumab, and for 30 days after discontinuing durvalumab). Inactivated viruses, such as influenza vaccines, are acceptable. - The following restrictions were applied for the specified times before, during and after patients received study treatment: - Female patients of childbearing age Sexually active women of childbearing potential with a non-sterilized male partner were to use at least one highly effective method of contraception from the time of screening and must agree to continue using such protection for 180 days after the last dose of durvalumab plus any drug combination therapy. Non-sterilized male partners of female patients were to use male condoms plus spermicide throughout this period. Discontinuation of birth control after this point was to be discussed with a trusted physician. Abstinence from sexual activity throughout the entire drug treatment and drug-free period was acceptable behavior; however, periodic abstinence, rhythmic contraception, and withdrawal were not accepted methods of birth control. Female patients also refrained from breastfeeding throughout this period. - Male patients with a fertile female partner Sexually active, non-sterilized men with a female partner of fertile potential were required to use spermicide in addition to male condoms from screening until 180 days after the last dose of durvalumab plus any combination therapy. Abstinence was acceptable behavior; however, periodic abstinence, rhythmic contraception, and withdrawal were not accepted methods of contraception. Male patients refrained from donating sperm throughout this period. Female partners (of fertile potential) of male patients were also required to use highly effective contraception throughout this period. - Women of childbearing potential were defined as women who had not been surgically sterilized (i.e. bilateral tubal ligation, bilateral oophorectomy or total hysterectomy) or who were postmenopausal. - Women were considered postmenopausal if they had been amenorrhea for 12 months and had no alternative medical cause. The following age-specific requirements applied: Women aged <50 years were considered postmenopausal if they had been amenorrhea for ≥12 months after discontinuation of exogenous hormone treatment and had luteinizing hormone and follicle-stimulating hormone levels within the institutional postmenopausal range or had undergone surgical sterilization (bilateral oophorectomy or hysterectomy). Women aged ≥50 years were considered postmenopausal if they had been amenorrhea for ≥12 months after cessation of all exogenous hormone therapy, had radiation-induced menopause at last menstruation >1 year ago, had chemotherapy-induced menopause at last menstruation >1 year ago, or had undergone surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy). For AZD6738: - The following restrictions applied for the specified times before, during and after patients were receiving study treatment: Patients must fast (drinking water only) for at least 2 hours before and at least 1 hour after dosing for all doses. - If vomiting occurs immediately after swallowing AZD6738, all remaining tablets should be counted and the dose replaced only if treatment can then be resumed at the scheduled dose. Scheduled doses may be taken up to 2 hours after the scheduled administration time. If more than 2 hours have passed, the missed dose should not be taken and the patient continued with their next dose at the assigned time. - If no clinically significant changes in blood pressure were observed after a single dose, no restrictions on driving were required. - All patients were advised not to consume grapefruit juice or Seville oranges (including marmalade, juice, etc.) while taking part in the study. Male patient: - Men were required to use condoms (containing spermicide) with all sexual partners during the study and for 1 week after their last dose of study drug. - If a male participant's sexual partner was a "female of childbearing potential" who was not using effective contraception, he was required to use condoms (containing spermicide) throughout the study and for 6 months after his last dose of study drug. - Not to donate sperm for 6 months after the last dose of study drug. Female patient: - Contraceptives susceptible to drug-drug interactions may be ineffective due to potential CYP3A4 interactions with AZD6738. Therefore, contraceptive methods used should include condoms and one of the following: Medroxyprogesterone injections (e.g., Depo-Provera) Intrauterine device (IUD) Levonorgestrel-releasing intrauterine system (e.g., Mirena) ○Fallen tube blockage o Partner who has had a vasectomy.

[0195] Efficacy Evaluation: This study evaluated the efficacy of AZD6738 when given in combination with durvalumab as a second-line regimen in patients with advanced gastric cancer.

[0196] Patient response to treatment was assessed by determining PFS and ORR using modified RECIST 1.1 criteria. Modified RECIST 1.1 guidelines are for measurable, non-measurable target and non-target lesions and objective tumor response criteria (complete response, partial response, stable disease or disease progression). Baseline methods of assessing tumor burden, CT or MRI scans of the chest, abdomen and pelvis, must be used at each subsequent follow-up assessment. After baseline evaluation, efficacy of all patients was assessed by objective tumor assessment every 8 weeks from the date of first dose until week 40, at which point evaluations were performed every 12 weeks until objective disease progression as defined by modified RECIST 1.1.

[0197] If patients discontinued treatment (and / or received subsequent cancer therapy) prior to progression, they were to be further followed until objective disease progression as defined by revised RECIST 1.1.

[0198] Objective tumor response assessment classification was based on the revised RECIST 1.1 with the following responses: CR (complete response), PR (partial response), SD (stable disease) and PD (progression of disease). Target lesion (TL) progression was calculated relative to the time of minimal tumor burden (i.e., the smallest sum of diameters ever recorded in the study). In the absence of progression, tumor response (CR, PR, SD) was calculated relative to baseline tumor measurements obtained before the start of treatment.

[0199] For patients with nonmeasurable disease only at baseline, classification of objective tumor response assessment was based on the revised RECIST 1.1 with the following responses: CR, PD and non-CR / non-PD. If the investigator has doubts as to whether progression has occurred, especially due to a response to NTL (non-target lesion) or the appearance of new lesions, it is advisable to continue treatment until the next scheduled evaluation or, if clinically indicated, immediately reassess the patient's status. If progression is confirmed by repeat scans, the date of the first scan should be published as the date of progression.

[0200] Any other sites suspected of new disease should also be imaged appropriately. If an unscheduled evaluation was performed and the patient had not progressed, every effort was made to perform a subsequent evaluation at the patient's scheduled visit. To achieve "overt progression" based on non-target disease, there had to have been substantial worsening of the overall level of non-target disease such that the overall tumor burden increased sufficiently to merit interruption of therapy, even if there was SD or PR in the target disease. A small "increase" in size of one or more non-target lesions is usually not enough to be considered a state of overt progression.

[0201] Safety assessment Blood and urine samples for the measurement of clinical chemistry, hematology and urinalysis were collected at times indicated in the assessment schedule and when clinically indicated. Clinical laboratory safety testing, including serum pregnancy testing, was to be performed in an approved clinical laboratory according to local standard procedures. Sample tubes and sample sizes may vary depending on the testing method used and local routine practice. Pregnancy testing may be performed on-site using approved tests (urine or serum pregnancy tests). Abnormal clinically significant laboratory results should be repeated as soon as possible (preferably within 24-48 hours). At the investigator's discretion, additional safety samples were collected if clinically indicated. Collection dates and times and results (values, units and reference ranges) were recorded on the appropriate CRF. Other safety tests were performed at screening, including evaluation of hepatitis B surface antigen, hepatitis C antibody and HIV antibody.

[0202] The laboratory's safety assessment included: Complete hematological evaluation: (a) Hemoglobin. (b) Red blood cells (RBC). (c) Platelets. (d) Mean corpuscular volume (MCV). (e) Mean corpuscular hemoglobin concentration (MCHC). (f) Mean corpuscular hemoglobin (MCH). (g) WBC. (h) Absolute white blood cell differential count (neutrophils, lymphocytes, monocytes, eosinophils, and basophils) and absolute or segmented neutrophil count, with band counts to be performed at each visit and when clinically indicated. If absolute differential counts were not available, differential percentages were to be provided. (i) Coagulation: - Activated partial thromboplastin time (APTT) was to be performed at baseline and if clinically indicated. - International normalized ratio (INR) was to be performed at baseline and if clinically indicated only if the patient was not taking warfarin. Patients taking warfarin were eligible to participate in the study, however, they were encouraged to closely follow their prothrombin time (INR and APTT) at least once a week for the first month, then monthly to see if their INR remained stable. (j) biochemical evaluation of safety; - Sodium - Potassium - Calcium - Magnesium - Creatinine - Total bilirubin - Gamma glutamyltransferase (GGT) - ALP -AST - ALT - Urea or Blood Urea Nitrogen (BUN) - Total Protein - Albumin - Lactate dehydrogenase (LDH).

[0203] Urinalysis: Urinalysis was performed at screening and if clinically indicated. If necessary, microscopic analysis was performed by the hospital's local laboratory.

[0204] Physical Examination: Follow paragraph

[0176] .

[0205] ECG: ECGs were performed at screening, baseline, at the time of combination treatment, and as clinically indicated throughout the study and were as described in paragraph

[0178] .

[0206] Vital Signs: Height was assessed at screening only. Weight was assessed at screening and any other time if clinically indicated. Any change in vital signs was recorded as an AE, if applicable. Supine BP and pulse rate were measured using a semi-automated BP recorder with appropriate cuff size after the patient had rested for at least 10 minutes and were assessed on Day 1 of each cycle (within a time window of ±7 days from the scheduled date). If assessed within 7 days prior to the first dose and met the defined eligibility criteria (if applicable), it did not need to be repeated on Day 1 of Cycle 1. The date and time of collection and measurement were recorded on the appropriate eCRF. Temperature was measured in degrees Celsius using an automated thermometer at screening and any other time if clinically indicated. The date and time of collection and measurement were recorded on the appropriate eCRF.

[0207] Other safety evaluations: Premenopausal women of childbearing potential were to undergo two pregnancy tests using blood or urine samples within 28 days before starting study treatment. Tests were performed by the hospital's local laboratory. If the result was positive, the patient was excluded / withdrawn from the study. If pregnancy was suspected during the study, tests were to be repeated.

[0208] Concomitant Medications: Any medications (except those excluded by the clinical trial protocol) deemed necessary for the subject's welfare and not interfering with the study medication were to be given at the investigator's discretion. The investigator had to record in the appropriate section of the CRF all concomitant medications taken by the subject from the date of signing the informed consent during the study.

[0209] During the study, the following were not permitted: (a) Prophylactic granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor. (b) Concomitant use of known strong CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin, and nelfinavir. (c) The following CYP3A4 inducers were avoided to avoid potential reduced exposure due to drug interactions: phenytoin, rifampicin, rifapentine, rifabutin, carbamazepine, phenobarbital, nevirapine, modafinil, and St. John's wort. (d) Traditional Chinese medicine with approved anti-cancer indications.

[0210] Clinical trial results: AZD6738 and durvalumab Thirty melanoma patients (10 cutaneous, 10 acral and 10 mucosal melanoma) were enrolled in the clinical trial according to the above protocol, all of whom were resistant to PD-L1 inhibitors. Thirty patients were evaluable for efficacy, with the following results: 9 confirmed partial responses (30%), 11 stable disease (37%) and 10 progressive disease (33%). The overall confirmed response rate was 30% (95% CI 15%-49%). The disease control rate (DCR) was 67% (20 of 30 patients; CI 47%-83%). Duration of response (DoR) >6 months was 67% (95% CI 28%-88%), with a median of 10.0 months (95% CI 3.2-NA). Median progression-free survival (PFS) was 7.0 months (95% CI 1.8-11.8; maturity 67%), while median overall survival (OS) was 14.0 months (95% CI 9.9-NA; maturity 47%).

[0211] Figures 1 and 2 show the clinical trial data for the combination of AZD6738 and durvalumab in graphical form.

[0212] Tables 1 and 2 show the clinical characteristics and resistance status of patients in clinical trials of the combination of selarasertib (AZD6738) and durvalumab. Responses were observed regardless of whether the patient was primary or secondary resistant. Furthermore, a greater proportion of patients receiving selarasertib and durvalumab with primary resistance responded compared to patients with secondary resistance, although primary resistance is known to be more difficult to treat. Responses were observed in all melanoma subtypes treated (acral, mucosal, and cutaneous melanoma). Responses were also observed in patients with high / low LDH (lactate dehydrogenase) and low PD-L1 expression at baseline, regardless of BRAF mutation / wild type.

[0213] [Table 4]

[0214] [Table 5]

[0215] [Table 6]

Claims

1. A combination of an ATR inhibitor and an immune checkpoint inhibitor for use in the treatment of melanoma in patients who have received prior immunotherapy.

2. The combination of claim 1, wherein the ATR inhibitor is selected from the group consisting of AZD6738, M6620 (berzosertib), BAY-1895344, EPT-46464, VE-821 and VX-970.

3. 3. The combination of claim 2, wherein the ATR inhibitor is AZD6738.

4. The combination according to any one of claims 1 to 3, wherein the immune checkpoint inhibitor is a PD-1 inhibitor, a PD-L1 inhibitor or a CTLA-4 inhibitor.

5. The combination according to any one of claims 1 to 4, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.

6. The combination of claim 5, wherein the PD-L1 inhibitor is durvalumab or an antigen-binding fragment thereof.

7. The combination according to any one of claims 1 to 6, wherein the melanoma is selected from the group consisting of cutaneous melanoma, acral melanoma and mucosal melanoma.

8. The combination according to any one of claims 1 to 7, wherein the melanoma is advanced melanoma.

9. The combination according to any one of claims 1 to 7, wherein the melanoma is metastatic melanoma.

10. A combination according to any one of claims 3 to 9, wherein AZD6738 is administered on days 15 to 28 of a 28 day cycle.

11. A combination according to any one of claims 3 to 9, wherein AZD6738 is administered on days 1 to 7 of a 28 day cycle.

12. A combination according to any one of claims 3 to 11, wherein the total daily dose of AZD6738 is from 30 mg to 500 mg.

13. 13. A combination according to claim 12, wherein the total daily dose of AZD6738 is administered twice daily at a dose of 240 mg.

14. 13. A combination according to claim 12, wherein the total daily dose of AZD6738 is administered twice daily at a dose of 160 mg.

15. The combination according to any one of claims 6 to 14, wherein durvalumab is administered in an amount of 1500 mg once every 4 weeks starting from day 1 of cycle 1.

16. The combination according to any one of claims 1 to 15, wherein the prior immunotherapy comprises treatment with an immune checkpoint inhibitor.

17. 17. The combination of claim 16, wherein the prior immunotherapy comprises treatment with an immune checkpoint inhibitor selected from a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor.

18. 18. The combination of claim 17, wherein the prior immunotherapy comprises treatment with an immune checkpoint inhibitor selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, and tremelimumab.

19. 19. The combination of claim 18, wherein the prior immunotherapy comprises treatment with pembrolizumab or nivolumab.

20. The combination according to any one of claims 1 to 19, wherein the patient has primary resistance to immunotherapy.

21. The combination according to any one of claims 1 to 19, wherein the patient has acquired resistance to immunotherapy.

22. The combination according to any one of claims 1 to 20, wherein the patient is receiving immunotherapy as an adjuvant therapy.

23. The combination according to any one of claims 1 to 22, wherein the treatment achieves a response rate of more than 30%.

24. The combination according to any one of claims 1 to 23, wherein the progression free survival is greater than 3 months, preferably greater than 4 months, preferably greater than 5 months, preferably greater than 6 months, more preferably greater than 7 months.

25. The combination according to any one of claims 1 to 24, wherein the overall survival is more than 10 months, preferably more than 11 months, preferably more than 12 months, preferably more than 13 months, more preferably more than 14 months.

26. The combination according to any one of claims 1 to 25, wherein the duration of response is at least 3 months, preferably at least 4 months, preferably at least 5 months, more preferably at least 6 months.

27. a. a first pharmaceutical composition comprising an ATR inhibitor and a pharma- ceutical acceptable excipient; b. a second pharmaceutical composition comprising an immune checkpoint inhibitor and a pharma- ceutical acceptable excipient; c. instructions for using said first and second pharmaceutical compositions in the treatment of melanoma in a patient who has previously undergone immunotherapy; and Kit including:

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